UNASSIGNED: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections are a great threat to public health worldwide. Ceftazidime-avibactam (CZA) is an effective β-lactam/β-lactamase inhibitors against CRKP. However, reports of resistance to CZA, mainly caused by Klebsiella pneumoniae carbapenemase (KPC) variants, have increased in recent years. In this study, we aimed to describe the resistance characteristics of KPC-12, a novel KPC variant identified from a CZA resistant K. pneumoniae.
UNASSIGNED: The K. pneumoniae YFKP-97 collected from a patient with respiratory tract infection was performed whole-genome sequencing (WGS) on the Illumina NovaSeq 6000 platform. Genomic characteristics were analyzed using bioinformatics methods. Antimicrobial susceptibility testing was conducted by the broth microdilution method. Induction of resistant strain was carried out in vitro as previously described. The G. mellonella killing assay was used to evaluate the pathogenicity of strains, and the conjugation experiment was performed to evaluate plasmid transfer ability.
UNASSIGNED: Strain YFKP-97 was a multidrug-resistant clinical ST11-KL47 K. pneumoniae confers high-level resistance to CZA (16/4 μg/mL). WGS revealed that a KPC variant, KPC-12, was carried by the IncFII (pHN7A8) plasmids (pYFKP-97_a and pYFKP-97_b) and showed significantly decreased activity against carbapenems. In addition, there was a dose-dependent effect of bla KPC-12 on its activity against ceftazidime. In vitro inducible resistance assay results demonstrated that the KPC-12 variant was more likely to confer resistance to CZA than the KPC-2 and KPC-3 variants.
UNASSIGNED: Our study revealed that patients who was not treated with CZA are also possible to be infected with CZA-resistant strains harbored a novel KPC variant. Given that the transformant carrying bla KPC-12 was more likely to exhibit a CZA-resistance phenotype. Therefore, it is important to accurately identify the KPC variants as early as possible.

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β-lactamase, a kind of hydrolase in multi-drug resistant pathogens, can hydrolyze β-lactam antibiotics and make these kinds of antibiotics invalid. Small-molecular inhibitors about the enzyme and their mechanism are widely investigated but they may result in unavoidable adverse reactions and drug-resistance. Herein, we propose a new therapeutic strategy of Chinese materioherbology, in which herbal medicine or traditional Chinese medicinal herbs can be employed as biological functional materials or refreshed/excited by means of materialogy. Natural tea nanoclusters (TNCs) were extracted from tea to inhibit β-lactamase. Different from the mechanism of small-molecular inhibitors inhibiting enzymes by binding to the corresponding active sites, the TNCs as a cap cover the protein pocket and create a spatial barrier between the active sites and antibiotics, which was named \"capping-pocket\" effect. TNCs were combined with amoxicillin sodium (Amo) to treat the methicillin-resistant Staphylococcus aureus (MRSA) pneumonia in mice. This combinatorial therapy remarkably outperforms antibiotic monotherapy in reducing MRSA infections and the associated inflammation in mice. The therapeutic strategy exhibited excellent biosafety, without any side effects, even in piglets. Hence, TNCs have great clinical value in potentiating β-lactam antibiotic activity for combatting multi-drug resistant pathogen infections and the \"pocket capping\" effect can guide the design of new enzyme inhibitors in near future.

UNASSIGNED: Antibiotics frequently induce abnormal liver function. Omadacycline is a novel aminomethylcycline antibiotic, which shows potent activity against Gram-positive and Gram-negative aerobic, anaerobic, and atypical (including Legionella pneumophila) bacteria. Of note, omadacycline is tolerable in most patients with liver impairment. However, evidence regarding the application of omadacycline in patients with Legionella pneumophila pneumonia after experiencing liver dysfunction is scarce.
UNASSIGNED: The current study reported 6 cases of patients with Legionella pneumophila pneumonia receiving omadacycline as subsequent antibiotics after experiencing liver dysfunction.
UNASSIGNED: These 6 cases were admitted to the hospital for pneumonia and received antibiotic therapy, including piperacillin-tazobactam, imipenem, meropenem, and moxifloxacin. After receiving these antibiotics, increased liver enzymes were noted. Although hepatoprotective therapy (such as magnesium isoglycyrrhizinate and glutathione) was given, the liver function was still abnormal. According to metagenomic next-generation sequencing, these patients were diagnosed with Legionella pneumophila pneumonia. Considering the abnormal liver function, the antibiotic therapy was switched to omadacycline-containing antibiotic therapy. After that, liver function was improved, and the infection was ameliorated. Ultimately, all patients discharged from the hospital, including 2 patients who achieved complete clinical symptomatic improvement and 4 patients who achieved partial clinical symptomatic improvement.
UNASSIGNED: This study emphasizes the successful treatment of switching to omadacycline after experiencing abnormal liver function in patients with Legionella pneumophila pneumonia. This study suggests that omadacycline may serve as an optional antibiotic for patients with Legionella pneumophila pneumonia, especially when occurring liver dysfunction. However, more clinical studies are required to validate our findings.

The COVID-19 pandemic, caused by SARS-CoV-2, has posed significant health challenges worldwide. While children generally experience less severe illness compared to adults, pneumonia remains a substantial risk, particularly for those under five years old. This study examines the clinical characteristics and treatment outcomes of pediatric COVID-19 pneumonia patients treated with favipiravir in Thailand, aiming to identify associated factors for pneumonia. A retrospective review was performed on pediatric patients aged 1 month to 18 years hospitalized with COVID-19 at Srinagarind Hospital, Khon Kaen University, from 13 January 2020 to 15 November 2021. Data on demographics, clinical symptoms, treatment, and outcomes were collected, and logistic regression analysis was used to identify factors associated with pneumonia. Among 349 hospitalized children, the median age was 8 years, with 51.9% being male. Symptoms included a fever (100%), a cough (74.2%), and a rash (24.9%). COVID-19 pneumonia was diagnosed in 54.7% of the children. Favipiravir was administered as the standard treatment, showing mild adverse effects, including a rash (4.3%) and nausea (2.8%). Monocytosis was significantly associated with COVID-19 pneumonia (aOR 30.85, 95% CI: 9.03-105.41, p < 0.001), with an ROC curve area of 0.77 (95% CI: 0.71-0.83). Pediatric COVID-19 patients typically exhibit mild-to-moderate symptoms, with pneumonia being common in the early pandemic phase. Monocytosis is a significant factor associated with COVID-19 pneumonia. Favipiravir demonstrated mild adverse effects. Further studies are needed to validate these findings across different settings and phases of the pandemic.

Carbapenem antibiotic resistance is an emerging medical concern. Bacteria that possess the Klebsiella pneumoniae carbapenemase (KPC) protein, an enzyme that catalyzes the degradation of carbapenem antibiotics, have exhibited remarkable resistance to traditional and even modern therapeutic approaches. This study aimed to identify potential natural drug candidates sourced from the leaves of Artemisia judaica (A. judaica). The phytoconstituents present in A. judaica dried leaves were extracted using ethanol 80%. A reasonable amount of the extract was used to identify these phytochemicals via gas chromatography/mass spectrometry (GC/MS). One hundred twenty-two bioactive compounds from A. judaica were identified and subjected to docking analysis against the target bacterial protein. Four compounds (PubChem CID: 6917974, 159099, 628694, and 482788) were selected based on favorable docking scores (-9, -7.8, -7.7, and -7.5 kcal/mol). This computational investigation highlights the potential of these four compounds as promising antibacterial candidates against the specific KPC protein. Additionally, in vitro antibacterial assays using A. judaica extracts were conducted. The minimum inhibitory concentration (MIC) against the bacterium K. pneumonia was 125 μg/mL. Well-disk diffusion tests exhibited inhibition zones ranging from 10.3 ± 0.5 mm to 17 ± 0.5 mm at different concentrations, and time-kill kinetics at 12 h indicated effective inhibition of bacterial growth by A. judaica leaf extracts. Our findings have revealed the pharmaceutical potential of Artemisia judaica as a natural source for drug candidates against carbapenem-resistant pathogens.

This study describes KPC-204, a novel variant of Klebsiella pneumoniae carbapenemase, characterized by a Lys-Asp-Asp (KDD) amino acid insertion at Ambler position 269 deviates from KPC-2. This variant was identified in an ST11-type clinical isolate of carbapenem-resistant Klebsiella pneumoniae from China. Notably, KPC-204 exhibits resistance to both ceftazidime-avibactam and carbapenems. Genetic analysis revealed that blaKPC-204 was located on a highly mobile IncFII/IncR plasmid within a complex genetic structure that facilitates its spread. Functional analysis, achieved through cloning into E. coli DH5α, validates KPC-204\'s contribution to increased resistance to ceftazidime-avibactam. The kinetic parameters showed that KPC-204 exhibited similar affinity to KPC-2 toward ceftazidime and reduced sensitivity to avibactam. Docking simulations revealed a weaker interaction between KPC-204 and avibactam compared to KPC-2. Mating experiments demonstrated the resistance\'s transmissibility. This investigation underscores the evolving diversity of KPC variants affecting ceftazidime-avibactam resistance, highlighting the necessity for continuous monitoring.

d-Lactic acid serves as a pivotal platform chemical in the production of poly d-lactic acid (PDLA) and other value-added products. This compound can be synthesized by certain bacteria, including Klebsiella pneumoniae. However, industrial-scale lactic acid production in Klebsiella pneumoniae faces challenges due to growth inhibition caused by lactic acid stress, which acts as a bottleneck in commercial microbial fermentation processes. To address this, we employed a combination of evolutionary and genetic engineering approaches to create an improved Klebsiella pneumoniae strain with enhanced lactic acid tolerance and production. In flask fermentation experiments, the engineered strain achieved an impressive accumulation of 19.56 g/L d-lactic acid, representing the highest production yield observed in Klebsiella pneumoniae to date. Consequently, this strain holds significant promise for applications in industrial bioprocessing. Notably, our genome sequencing and experimental analyses revealed a novel correlation between UTP-glucose-1-phosphate uridylyltransferase GalU and lactic acid resistance in Klebsiella pneumoniae. Further research is warranted to explore the potential of targeting GalU for enhancing d-lactic acid production.

The emergence of new SARS-CoV-2 variants can affect vaccine efficacy, laboratory diagnosis and the therapies already available, triggering interest in the search for antiviral agents for SARS-CoV-2 infections. Ribavirin (RBV) is a broad-spectrum antiviral with demonstrated in vitro activity against multiple viruses, including SARS-CoV-2. This retrospective study evaluated the dynamics and viral clearance of SARS-CoV-2 in hospitalised adult participants (PTs) with COVID-19 pneumonia who received an RBV aerosol within a compassionate use study. The impact of RBV on the clinical outcome and the mutational profile of SARS-CoV-2 was also assessed. The median RNA values measured in nine PTs included in this study decreased from baseline to discharge (at BL, threshold cycle (Ct) = 22.4, IQR 19.84-5.07; at discharge, Ct = 27.92, IQR 26.43-36.11), with a significant decline in the Ct value evaluated by Friedman rank ANOVA analysis, p = 0.032. Seven out of nine PTs experienced a clinical improvement, while two PTs deceased during hospitalisation. In PTs with a favourable outcome, the virus clearance rate at discharge was 28.6%. The cumulative clearance rate was 71.4% within 14 days from discharge. A mutational pattern after RBV was detected in three out of five PTs in whom whole-genome sequencing was available. Our findings suggest that RBV limits SARS-CoV-2 replication, possibly resulting in a favourable clinical outcome. Ribavirin may also contribute to the mutational spectrum of SARS-CoV-2.

Plastic bronchitis (PB) constitutes a life-threatening pulmonary disorder, predominantly attributed to Mycoplasma pneumoniae (MP) infection. The pathogenic mechanisms involved remain largely unexplored, leading to the absence of reliable approaches for early diagnosis and clear treatment. Thus, the present investigation aimed to develop an MP-induced mouse model of PB, thereby enhancing our understanding of this complex condition. In the first stage, healthy BALB/c mice were utilized to investigate the optimal methods for establishing PB. This involved the application of nebulization (15-20 min) and intratracheal administration (6-50 μL) with 2-chloroethyl ethyl sulfide (CEES) concentrations ranging from 4.5% to 7.5%. Subsequently, the MP model was induced by administering an MP solution (2 mL/kg/day, 108 CFU/50 μL) via the intranasal route for a duration of five consecutive days. Ultimately, suitable techniques were employed to induce plastic bronchitis in the MP model. Pathological changes in lung tissue were analyzed, and immunohistochemistry was employed to ascertain the expression levels of vascular endothelial growth factor receptor 3 (VEGFR-3) and the PI3K/AKT/mTOR signaling pathway. The administration of 4.5% CEES via a 6 µL trachea was the optimal approach to establishing a PB model. This method primarily induced neutrophilic inflammation and fibrinous exudate. The MP-infected group manifested symptoms indicative of respiratory infection, including erect hair, oral and nasal secretions, and a decrease in body weight. Furthermore, the pathological score of the MP+CEES group surpassed that of the groups treated with MP or CEES independently. Notably, the MP+CEES group demonstrated significant activation of the VEGFR-3 and PI3K/AKT/mTOR signaling pathways, implying a substantial involvement of lymphatic vessel impairment in this pathology. This study successfully established a mouse model of PB induced by MP using a two-step method. Lymphatic vessel impairment is a pivotal element in the pathogenetic mechanisms underlying this disease entity. This accomplishment will aid in further research into treatment methods for patients with PB caused by MP.